Stealthy Gene Network Makes Brain Tumors Flourish

Researchers discover kingpin genes spur growth in most lethal tumor

CHICAGO --- The brain tumor afflicting Sen. Edward Kennedy – a glioblastoma – is the most aggressive and wily form of brain cancer. It has foiled researchers’ decades-long efforts to thwart its explosive growth in the brain. The lethal tumor – the most common brain tumor in humans -- nimbly alters its genes like a quick-change artist to elude treatments to destroy it.

But scientists from Northwestern University Feinberg School of Medicine have discovered the formidable tumor’s soft underbelly. They have identified a network of 31 mutated genes that stealthily work together to create the perfect molecular landscape to allow the tumor to flourish and mushroom to the size of an apple in just a few months.

Northwestern researchers have also identified a new gene, Annexin A7, a vital guard whose job is to halt tumor growth and whose level in the tumor predicts how long a glioblastoma patient will survive. The genetic landscape of glioblastomas eliminates Annexin A7 by wiping out its home base, chromosome 10.

The discoveries help researchers understand the tumor's vulnerabilities and offer new targets for therapies to treat the disease.

"These 31 genes are the kingpins in what you could call an organized crime network of genes that enable the tumor to grow with breathtaking speed," said Markus Bredel, M.D., director of the Northwestern Brain Tumor Institute research program, assistant professor of neurological surgery at the Feinberg School and the principal investigator of the two studies reporting these new findings. "These 31 genes are highly connected to and affect hundreds of other genes involved in this process." Bredel also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The studies will be published in the July 15 issue of Journal of the American Medical Association.

It was no small task for Bredel to identify the kingpins of the network. Glioblastomas are among the most biologically complex cancers, involving changes in thousands of genes. Leukemia, by contrast, involves changes in just a few genes.

Bredel said the way to identify the key players was to determine which genes had the most connections to other genes in the network. "We don't care about the gangster on the street. We wanted to find the big bosses," Bredel said. "If you knock them out, then you have a big effect on all the other genes in the network."

To accomplish that, Bredel and colleagues looked at the molecular levels and genetic profiles of more than 500 brain tumors of patients from around the country as well as the clinical profiles of the patients. Bredel's first study reports on the 31 key mutated genes he discovered that comprise the tumor’s primary network. These genes represent a recurrent pattern of the most important mutations in the tumor.

"If many of those genes were mutated, the more aggressive the tumor and the less time the patient would survive," Bredel said. These are called hub genes because they are at the hub of all the mutated gene interaction.

In the second study, Bredel reports on the interaction of two of the 31 genes that are most frequently and concurrently affected by genetic alterations. One of those genes is EGFR (epidermal growth factor receptor), a well-known player in many cancers and known as an oncogene. EGFR has physiological importance in normal development. In nearly half of the glioblastoma patients, EGFR is mutated and abnormally activated, as if its dial is cranked permanently to "high."

Bredel discovered that the other gene, Annexin A7, is a vital guard whose job is to halt tumor growth by regulating the EGFR gene. Bredel found Annexin A7 was lost or diminished in many of the patients' malignant brain tumors. The reason was its home base -- chromosome 10 -- had been wiped out in about 75% of the tumors.

The study showed the presence and quantity of Annexin A7 in the malignant brain tumor accurately predicts how long a glioblastoma patient will survive. The more Annexin A7, the more restrictions on the tumor growth and the longer the survival. Bredel said the identification of Annexin A7 as a major regulator of EGFR provides a biological reason for the frequent parallel loss of chromosome 10 and gain of the EGFR gene in glioblastomas.

In the laboratory, Bredel tested the relationship between EGFR and Annexin A7 to try to understand exactly how they affected the tumor. Working with brain tumor cells, Bredel increased the level of EGFR and, in parallel, knocked out Annexin A7. The tumor cells grew much faster compared to tumor cells in which only one gene was modified.

"It's like a 'buy two, get one free' sale," Bredel said. "The tumor says, 'I'm making a good deal. I'm going to buy those two mutations because it's going to be very rewarding for me'."

With one mutation that increased EFGR and the other that eliminated chromosome 10 and Annexin A7, the tumor was free to proliferate unchecked.

“Understanding the key role of Annexin A7 in malignant brain tumors offers the opportunity for a new therapeutic target,” Bredel said. "The challenge is now that we've established that this gene is important, how can we modulate it through molecular cancer therapy?"

"We want to extend the survival of the patients, transform this hyper-acute disease into a more chronic tumor disease," Bredel said. "Maybe someday, a glioblastoma patient will be able to live for 10 or 20 years after a diagnosis."